Dermatological compositions comprising avermectin nanocapsules

ABSTRACT

Compositions and nanoemulsions containing lipid nanocapsules dispersed in a hydrophilic phase, such nanocapsules including at least one avermectin compound, are useful for the treatment of dermatological pathologies, e.g., rosacea.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/385,533, filed Apr. 10, 2009, which is a continuation of PCT/FR2007/052138, filed Oct. 12, 2007, and designating the United States(published in the French language on Apr. 17, 2008, as WO 2008/043973A1; the title and abstract were published in English), which claimspriority under 35 U.S.C. §119 of application Ser. No. 06/54237, filed inFrance on Oct. 12, 2006, each earlier application hereby expresslyincorporated by reference in its entirety and each assigned to theassignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to pharmaceutical, in particular,dermatological compositions based on a compound of the avermectin familyin the form of a nanoemulsion comprising oily nanocapsules dispersed inan aqueous phase. This invention also relates to a method for thepreparation thereof and to its formulation into medicaments useful forthe treatment of dermatological conditions/afflictions, in particular ofrosacea.

2. Description of Background and/or Related and/or Prior Art

Ivermectin is a mixture of two compounds belonging to the avermectinclass, 5-O-demethyl-22,23-dihydroavermectin A_(1a) and5-O-demethyl-22,23-dihydroavermectin A_(1b). They are also known underthe trademark of 22,23-dihydroavermectin B_(1a) and22,23-dihydroavermectin B_(1b). Ivermectin contains at least 80% of22,23-dihydroavermectin B_(1a) and less than 20% of22,23-dihydroavermectin B_(1b). This active agent forms part of theavermectin class, a group of macrocyclic lactones produced by thebacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale,The extra pharmacopoeia, 29th Edition, Pharmaceutical Press, London).Avermectins include in particular ivermectin, invermectin, avermectin,abamectin, doramectin, eprinomectin and selamectin.

Ivermectin is more particularly an antihelminthic. It has already beendescribed in humans in the treatment of Onchocerca volvulusonchocerciasis, gastrointestinal strongyloidiasis (anguillulosis)(product Stromectol®), human sarcoptic scabies (Meinking TL et al., N.Engl. J. Med., 1995 July 6; 333(1):26-30 The treatment of scabies withivermectin) and in the treatment of diagnosed or suspectedmicrofilaremia in subjects suffering from lymphatic filariasis caused byWuchereria bancrofti.

Ivermectin exhibits great instability in the presence of water, and itis particularly difficult to obtain stable pharmaceutical compositionscontaining it. Indeed, this active ingredient has a very low solubilityin water (0.005 mg/ml) and is degraded in a hydrophilic medium. Thissensitivity to aqueous media can therefore lead to chemical instabilityof the active agent and/or to crystallization of the active agentinitially solubilized, and limits its formulation in cosmetic ordermatological compositions applied by the topical or oral route.

U.S. Pat. No. 4,389,397 describes the efforts carried out to increasethe solubility of ivermectin in an aqueous medium, and in particularproposes solubilizing ivermectin in a mixture of surfactant and organiccosolvents.

Moreover, other concepts have been advanced, such as the solubilizationof the active ingredient in a fatty phase (see FR0603452) to improve thestability of this active agent.

However, to prevent the degradation of ivermectin in an aqueousformulation for skin application, it appears advantageous to manipulatethe structure of the interface from the ivermectin solubilizing mediumand the aqueous phase.

CN 1491551 presents formulations of the ivermectin nanocapsule type insuspension in water produced via polymeric emulsions, that is to say, asolvent-free process employing an in situ polymerization of monomer.

Likewise, FR 2,805,761 describes lipid nanocapsules containingphosphatidylcholines in combination with a hydrophilic cosurfactantderived from polyethylene glycol, Solutol HS 15. However, the presenceof a cosurfactant is necessary for the production of the nanocapsules.Moreover, the process for preparing such nanocapsules is carried out byphase inversion (PIT process), which results in the use of temperaturecycles in this process. Finally, the active agents are solubilized in anoil composed of medium-chain triglycerides of caprylic and capric acids,which is marketed under the trademark Labrafac WL1349 by GATTEFOSSE.

SUMMARY OF THE INVENTION

It has now surprisingly been discovered that compositions in the form ofnanoemulsions comprising ivermectin solubilized in the dispersed oilyphase make it possible to chemically stabilize this active agent, andare easy to prepare. Such nanoemulsions comprise ivermectin insolubilized form in a hydrophilic environment, do not require the use ofa polymer or an organic solvent, and ensure the chemical stability ofthe active agent. They can also promote skin penetration by ivermectin,which is useful in the treatment of dermatologicalconditions/afflictions, in particular rosacea.

The present invention thus features compositions, in particularpharmaceutical compositions, comprising at least one compound of theavermectin family, such compositions being in the form of ananoemulsion.

The compounds of the avermectin family are in particular selected fromamong ivermectin, invermectin, avermectin, abamectin, doramectin,eprinomectin and selamectin, and preferably ivermectin.

The present invention therefore also features compositions exhibitingphysical stability and chemical stability of the active agent over time.

The expression “physical stability” according to the invention means acomposition exhibiting no change in macroscopic appearance (phaseseparation, change in visual color and the like) or microscopicappearance (recrystallization of the active agents) after storing attemperatures of 4° C. and 40° C. for 2, 4, 8 and 12 weeks.

The expression “chemical stability” according to the invention means acomposition in which the content of active ingredient remains stableafter three months at room temperature and at 40° C. A stable content ofactive ingredient means according to the invention that the contentexhibits very little variation compared with the initial content, thatis to say, that the variation in the content of active ingredient attime T should not be less than 90% to more particularly 95% of theinitial content at T0.

The compositions according to the invention comprise from 0.01 to 10% ofat least one avermectin by weight relative to the total weight of thecomposition. Preferably, the compositions according to the inventioncontain from 0.1 to 5% of at least one avermectin, preferablyivermectin.

The expression “nanoemulsion” means a colloidal lipid system comprisinglipid nanocapsules with a solid or semisolid interface, which aredispersed in a continuous hydrophilic phase, the said nanocapsulescontaining an oily inner phase in which the avermectin is solubilized,and an envelope forming the semisolid or solid interface from the oilyinner phase and the continuous hydrophilic phase.

In particular, the present invention features nanoemulsions preparedwith no organic solvent.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

According to the present invention, the compositions comprisenanocapsules and not nanospheres. The expression “nanocapsules” meansparticles consisting of a core (inner phase) that is liquid orsemiliquid at room temperature, coated with a film (envelope or layer)that is solid at room temperature, in contrast to nanospheres which arematrix particles, that is to say, the entire mass of which is solid.When nanospheres contain a pharmaceutically acceptable activeingredient, the latter is finely dispersed in the solid matrix.

The expression “lipid nanocapsule” means a nanocapsule whose core iscomposed of one or more fatty substances that are liquid or semiliquidat room temperature, and in which the film (envelope) is of a lipophilicand non-polymeric nature. Indeed, lipid nanocapsules require no polymerand therefore no polymerization in situ.

The expression “room temperature” means a temperature of from 15 to 25°C.

The lipid nanocapsules according to the present invention have a meansize of less than 200 nm, preferably less than 150 nm.

The lipid nanocapsules (simply called “nanocapsules” in the text whichfollows) are present in the compositions according to the invention in aquantity of from 10 and 30% by weight relative to the total weight ofthe composition, and preferably from 10 and 20%.

The nanocapsules each consist of a core which is liquid or semiliquid atroom temperature, coated with a film which is solid at room temperature.

The film (layer) coating the nanocapsules is the only constituent of theformulation that is solid at room temperature. It is not of a polymericnature. It is constituted by one or more lipophilic surfactants;advantageously, such lipophilic surfactant(s) is (are) selected from thelecithin family, and preferably the lipophilic surfactant is ahydrogenated lecithin, advantageously in which the percentage ofsaturated (or hydrogenated) phosphatidylcholine is high. The expression“high percentage” means a quantity of 70 to 99% of saturated (orhydrogenated) phosphatidylcholine relative to the total weight oflecithin. Phosphatidylcholines show good compatibilities with the skinwith a very low irritant potential.

As the lecithin used in the present invention is solid at roomtemperature, this promotes the formation of a semisolid interface in thenanoemulsion.

As lecithins which can be used, exemplary are, in particular, natural orsynthetic soybean or egg lecithins having a hydrogenatedphosphatidylcholine content greater than 70%, such as for example LIPOIDof the S75-3, S100-3 or SPC-3 grade, Epikuron of the 200 SH or 100Hgrade, or Phospholipon of the 80H, 90H or 100H grade.

The lipophilic surfactant film coating the nanocapsules as defined aboveis present in a quantity of from 0.1 to 10% by weight, preferably from 1to 5% by weight relative to the total weight of the composition.

The film of lipophilic surfactant, in particular of lecithin, accordingto the invention allows on its own the encapsulation of avermectin,preferably ivermectin, which avoids contact from this avermectin and thehydrophilic phase, and thus ensures the chemical stability of thisactive agent. In particular, the composition, and in particular thefilm, contains no cosurfactant apart from the lecithins, and inparticular no hydrophilic cosurfactant.

Avermectin is thus solubilized in the core of the nanocapsules (innerphase), the said core being liquid or semiliquid at room temperature.

Several preformulation studies (“Preformulation stability screening ofivermectin with non-ionic emulsion excipient” N. O. Shaw, M. M. deVilliers and A. P. Lötter in Pharmazie 54 (1999) pp372-376) have shownthat ivermectin is incompatible with certain lipophilic excipients. Theanalytical results presented in this publication show a degradation ofivermectin in particular in ceteareth-25, ceteareth-6, PEG-8-distearate,PEG-8-stearate, PEG-660-OH-stearate, PEG-4000, polyoxyethylene-10,glycerol monostearate S/E, propylene glycol dicaprylate, cetearyloctanoate, polyglycerol-3-diolate, a mixture of C18-C36 triglycerides,Gamma cyclodextrin, soybean lecithin, cholesterol and stearic acid.

In particular, in this publication, soybean lecithin is mentioned as oneof the excipients which can degrade ivermectin. Now, in the presentinvention, the lecithins used are preferably hydrogenated lecithins. Asthe studies carried out in Example 1 show, surprisingly, suchhydrogenated lecithins do not degrade ivermectin.

The composition of the inner phase (core which is liquid or semiliquidat room temperature) is therefore essential for the stability of theactive ingredient. It has been shown, in particular in Example 1, thatwhen the core is essentially constituted by a particular fatty substancewhich is liquid or semiliquid at room temperature and in whichavermectin is solubilized, the stability of the active agent ismaintained. Such a fatty substance is in particular diisopropyl adipate,marketed under the trademark Crodamol DA by Croda, or under thetrademark Ceraphyl 230 by ISP, or under the trademark Wickenol 116 byAlzo, PPG 15 stearyl ether marketed under the trademark Arlamol E byUniqema, octyl dodecanol marketed under the trademark Eutanol G byCognis, C12-C15 alkyl benzoate marketed under the trademark Tegosoft TNby Degussa, dicaprylyl ether marketed under the trademark Cetiol OE,octyl palmitate marketed under the trademark Crodamol OP, ethoxydiglycolmarketed under the trademark Transcutol HP, lanolin, benzyl benzoate andmixtures thereof.

In addition to this (these) fatty substance(s), the inner phase may alsocomprise one or more fatty substances which are liquid or semiliquid atroom temperature and do not solubilize the active agent, such as inparticular triglycerides having from 18 to 36 carbon atoms, cetylalcohol marketed under the trademark Speziol C16 by Cognis.

Preferably, the fatty substance of the inner phase is solely constitutedby diisopropyl adipate.

Such a fatty substance is present in a quantity of from 90 to 99.99% byweight relative to the total weight of the inner phase.

The continuous hydrophilic phase comprises water. This water may bedemineralized water, floral water such as cornflower water, or a thermalor natural mineral water, for example selected from Vittel water, waterfrom the Vichy basin, Uriage water, Roche Posay water, Bourboule water,Enghien-les-Bains water, Saint Gervais-les-Bains water, Néris-les-Bainswater, Allevard-les-Bains water, Digne water, Maizières water,Neyrac-les-Bains water, Lons-le-Saunier water, Eaux-Bonnes water,Rochefort water, Saint Christau water, Fumades water andTercis-les-bains water, Avène water or Aix-les-Bains water.

The water may be present in an amount of from 70 to 90% by weightrelative to the total weight of the composition, preferably from 80 to90% by weight.

The hydrophilic phase may also comprise other hydrophilic compounds suchas preservatives or humectants.

Among the preservatives which can be used, parabens or phenoxyethanolare particularly exemplary.

Among the humectants which can be used, glycerine is particularlyexemplary.

In one of the preferred embodiments according to the invention, thecomposition may also comprise a gelling agent. This gelling agent ispreferably a cellulose derivative selected from among semi-syntheticcellulose gelling agents such as methylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,carboxymethylcellulose, hydroxymethylcellulose andhydroxypropylcellulose, taken alone or as a mixture.Hydroxypropylmethylcellulose or hydroxyethylcellulose is preferablyused. These compounds are marketed in particular by Dow Chemical underthe trademark Methocel® (for example: Methocel® E4M) or by Herculesunder the trademark Natrosol® (for example: Natrosol® 250 HHX). Thegelling agent may also be selected from natural gums such as gumtragacanth, guar gum, acacia gum, gum arabic, starch and itsderivatives, copolymers of polyacrylic acid and methyl methacrylate,carboxyvinyl polymers, polyvinyl pyrrolidones and their derivatives,polyvinyl alcohols, sodium alginate, pectin, dextrin, chitosan, takenalone or as a mixture, polyacrylamides such as the polyacrylamide/C13-14isoparaffin/laureth-7 mixture such as for example that marketed bySEPPIC under the trademark Sepigel 305 or the acrylamide, AMPS copolymerdispersion 40%/isohexadecane mixture under the trademark Simulgel600PHA, or the family of modified starches such as Structure Solanacemarketed by National Starch or mixtures thereof.

The gelling agent is used in particular at a concentration of from 0.1to 10% by weight, preferably from 0.1 to 2% by weight.

The presence of a gelling agent in the compositions according to theinvention make it possible to improve the physical stability of thecomposition over time.

The pharmaceutical compositions according to the invention are usefulfor the treatment of the skin and may be administered by the topical,parenteral or oral route, whether regime or regimen. Preferably, thecomposition is administered by the topical route.

By the oral route, the pharmaceutical composition may be provided inliquid or pasty form, and more particularly in the form of gelatincapsules, sugar-coated tablets or syrups.

By the parenteral route, the composition may be provided in the form ofsuspensions for infusion or for injection.

By the topical route, the composition may be provided in liquid or pastyform, and more particularly in the form of creams, milks, ointments,impregnated pads, syndets, wipes, gels, sprays, foams, lotions, sticks,shampoos or cleansing bases.

The composition in nanoemulsion form thus preferably comprises in water,by weight relative to the total weight of the composition:

-   -   a) 0.1 to 5% of lipophilic surfactant which is solid at room        temperature, preferably lecithin;    -   b) 1 to 20% of a fatty substance which is liquid or semiliquid        at room temperature, preferably diisopropyl adipate;    -   c) 0.1 to 5% of at least one avermectin, preferably ivermectin;    -   d) 0 to 2% of gelling agent, preferably a cellulose derivative.

The pharmaceutical compositions according to the invention mayadditionally contain inert additives or combinations of these additives,such as:

-   -   preservatives;    -   propenetrating agents;    -   stabilizing agents;    -   moisture-regulating agents;    -   pH-regulating agents;    -   osmotic pressure-modifying agents;    -   UV-A and UV-B screening agents; and    -   antioxidants.

Among the propenetrating agents according to the invention, particularlyexemplary are propylene glycol, N-methyl-2-pyrrolidone or dimethylsulfoxide.

Of course, one skilled in this art will be careful to select theoptional compound(s) to be added to these compositions such that theadvantageous properties intrinsically attached to the present inventionare not, or not substantially, impaired by the addition envisaged.

These additives may be present in the composition from 0.001 to 20% byweight relative to the total weight of the composition.

The present invention also features a method for preparing nanoemulsionscomprising at least one avermectin, preferably ivermectin. This methodinvolves a High-Pressure Homogenizer (HPH). In particular, the methodaccording to the invention does not use a Phase Inversion Temperature(PIT) (used in particular in FR 2,805,761 and FR 2,840,531) andtherefore does not require a cycle or cycles of temperature increase anddecrease. Indeed, the method according to the invention is performed inthe HPH in the cold state; the HPH therefore does not require successiveheating and cooling, and is not thermoregulated.

The method according to the present invention comprises the followingsteps:

-   -   (i) Solubilization of avermectin in the fatty substance which is        liquid or semiliquid at room temperature, so as to obtain the        oily phase.

Preferably, ivermectin is solubilized in the fatty substance, forexample in Crodamol DA.

-   -   (ii) Mixing of the hydrophilic compounds, so as to obtain the        hydrophilic phase.

In particular, the preservative(s) is (are) mixed with water.

The two phases (lipophilic and hydrophilic) are then preferably heatedseparately to a temperature preferably of about 75° C.

-   -   (iii) Dispersion of the lipophilic surfactant in the oily phase        obtained in (i) or in the hydrophilic phase obtained in (ii).

The lipophilic surfactant, in particular lecithin, is dispersed in thehydrophilic phase or in the inner oily phase; for example, Phospholipon90H is dispersed in the oily phase, while Lipoid S75-3 is dispersed inthe aqueous phase.

-   -   (iv) Mixing the oily and hydrophilic phases.

Once both phases reach the temperature, they are mixed with stirring.Once this prehomogenization has been performed, the emulsion isintroduced into the High-Pressure Homogenizer (HPH).

-   -   (v) Introduction of the mixture obtained in (iv) into the        High-Pressure Homogenizer, so as to obtain a nanoemulsion.

The use of a High-Pressure Homogenizer requires fixing the number ofpassages through the homogenization chamber and the homogenizationpressure. The homogenization process is then applied:

-   -   minimum 500 bar up to 1,000 bar of homogenization pressure in        the homogenization chamber,    -   from 5 and 10 passages through the homogenization chamber.

During the passages through the homogenization chamber, the nanoemulsionis not heated and the temperature of the HPH system is not controlled.

-   -   (vi) Gelling: optionally, addition of a gelling agent to the        composition obtained in (v).

When it is present, the nanoemulsion gelling step occurs at the end ofthe manufacture after the various passages through the HPH, duringcooling of the nanoemulsion.

The gelling agent is then added, with sufficient stirring, to ahomogeneous dispersion, during cooling of the nanoemulsion. The stirringis maintained for the period required to complete the step of gelling ofthe system.

The present invention also features formulation of the nanoemulsion intomedicaments useful for treating human dermatologicalconditions/afflictions.

The nanoemulsions according to the invention are particularly useful forthe treatment of rosacea, acne vulgaris, seborrhoeic dermatitis,perioral dermatitis, acneform rash, transient acantholytic dermatitisand acne miliaris necrotica.

Administration of the nanoemulsions according to the invention is moreparticularly intended for the treatment of rosacea.

These are going to now be given, by way of illustration and without anylimitative characters, various formulations of compositions comprisingnatural avermectins.

EXAMPLE 1 Study of Ivermectin Preformulation

There are numerous excipients used in the formulation of emulsions orliposomes which result in degradation of ivermectin. The Table belowpresents the results of tests of stability and solubility of ivermectinin various excipients:

Solubility T0 T 1 month T 3 months max (mg/g) (mg/g) T ambient 40° C. Tambient 40° C. Solutol HS15 10.8 9.8 9.4 7.1 ND ND (PEG-15 (95%) (72%)hydroxystearate Benzyl alcohol 32.8 9.9 9.8 9.7 ND ND (99%) (98%)Labrasol (PEG-8 ND 8.1 8.1 7.9 8.1 5.6 caprylic/capric (100%)  (98%)(100%)  (69%) glycerides) Labrafac Hydro 70  9.0 8.5 6.7 6.3 4.2 WL1219(caprylic/ (95%) (75%) (70%) (47%) capric triglyceride PEG-4 esters)Miglyol 812 17.9 8.7 8.3 8.2 8.3 8.4 (95%) (94%) (96%) (96%) LipoidS75-3 + ND 9.4 9.5 9.5 9.2 9.7 benzyl alcohol (101%)  (101%)  (98%)(103%)  Ph90H + benzyl ND 9.25 9.7 9.5 alcohol (105%)  (103%)  CrodamolDA 94.2 Stable over 1 month Benzyl benzoate 44.2 ND Ph90H: Phospholipon90H ND = not determined

According to the above Table, it is not possible to use Solutol HS15 ina nanoemulsion containing ivermectin. Indeed, the Table above shows adegradation at 1 month of 28% of ivermectin. Moreover, it seems thativermectin, on the one hand, is not perfectly stable in Mygliol 812,which corresponds to an oil composed of medium-chain triglycerides ofcaprylic and capric acids (C8 and C10), and, on the other hand, has arelatively low solubility in this oil.

On the other hand, it appears possible to formulate ivermectin in ananoemulsion with soybean lecithin (LIPOID S75-3) and diisopropyladipate (Crodamol DA) to ensure chemical stability of this active agent.The choices of the inner oily phase and of the surfactant to be used aretherefore validated.

EXAMPLE 2 Formulations

Formu- Formu- Formu- Constituents lation 1 lation 2 lation 3 Formulation4 Ivermectin 1.1% 1.1%   1%   1% Crodamol DA 13.9%  13.9%   14%  14%Phospholipon 90H 1.9% 1.9% Lipoid S75-3 1.9% 1.9% Nipagin N M 0.2% 0.2%0.2% 0.2% Gelling agent - for 0.5% 0.5% example cellulose derivative:Natrosol 250 HHX Water Qs 100% Qs 100% Qs 100% Qs 100%

EXAMPLE 3 Method for the Manufacture of the Formulations of Example 2

The method in this example employs a High-Pressure Homogenizer (HPH).

Manufacturing steps:

Solubilization of ivermectin:

Ivermectin is solubilized in the oily phase, here in Crodamol DA.

2. Preparation of the hydrophilic phase:

The preservative is solubilized in water.

3. Dispersion of the hydrogenated phosphatidylcholine:

The hydrogenated phosphatidylcholine is dispersed in the hydrophilicphase or in the oily phase according to the content ofphosphatidylcholine.

Both phases are heated separately to about 75° C.

4. Mixing of the phases:

Once both phases reach the temperature, they are mixed with stirring(turrax homogenization 2 minutes at 8000 rpm).

Once this prehomogenization has been performed, the emulsion isintroduced into the HPH.

5. High-Pressure Homogenization:

The use of a High-Pressure Homogenizer requires fixing the number ofpassages through the homogenization chamber and the homogenizationpressure.

The homogenization process is then applied:

-   -   minimum 500 bar up to 1,000 bar of homogenization pressure in        the homogenization chamber,    -   from 5 and 10 passages through the homogenization chamber.

During the passages through the homogenization chamber, the nanoemulsionis not heated and the temperature of the HPH system is not controlled.

6. Gelling:

When it is present, the nanoemulsion gelling step occurs at the end ofthe manufacture after the various passages through the HPH, duringcooling of the nanoemulsion.

The gelling agent is then added, with sufficient stirring, to ahomogeneous dispersion, during cooling of the nanoemulsion.

The stirring is maintained for the period required to complete the stepof gelling of the system.

EXAMPLE 4 Studies of Stability of the Formulations of Example 2

1—Physical:

Granulometric analysis: Zetasizer: Nanoseries-Nano-ZS (Malvern)

Two dilutions are used to carry out the granulometric analyses:

-   -   1d: 10 μl of the nanoemulsion in 15 ml of filtered distilled        water    -   2d: 1 ml of 1d in 5 ml of distilled water

Formulation 1 (Lipoid S75-3):

T0 Size (nm) 141 CV % 5% Temperature stability 4° C. T. ambient 40° C. T3 Size (nm) 133 124 442 131 485 months CV % 6 13 20 17 20 % by number100% >99% <1% >95% <5% CV = Coefficient of Variation

There are two particle size populations which are not always detectedduring the measurements as a function of the dilutions analyzed. Theappearance of the population from 400 and 800 nm is not reproducible.(High CV for dilution 1d and disappearance for dilution 2d).

Formulation 2 (Phospholipon 90H):

T0 Size (nm) 157 600 CV % 6.5 25 % by number >95% <5% Temperaturestability 4° C. T. ambient 40° C. T 1 Size (nm) 150 309 133 650 250 433month CV %  11  20  9  18  9  15 % by number >95% <5% >95% <5% >95% <5%T 2 Size (nm) 242 479 221 630 159 519 months CV %  11  10  8  10  2  10% by number >99% <1% >99% <1% >95% <5%

Formulations 3 and 4 with Natrosol 250HHX:

The physical stability of the gelled formulations 3 and 4 is obtained onthe basis of microscopic observations at T0, 6 and 9 months attemperatures of 4° C., ambient and 40° C.

Even after 9 months of stability at the 3 temperatures, formulations 3and 4 exhibit no degradation and show a finer droplet size than thecompositions with no gelling agents.

The physical stability of the compositions according to the inventiontherefore appear to have been improved with the increase in theviscosity of the composition by addition of the gelling agent.

2—Chemical:

Chemical assay of the compositions according to the invention.

Formulation 1 (Lipoid S75-3):

T0 mg/g 10.92 % titre 102 expected 4° C. T. ambient 40° C. T1 month %titre 105 104 105 expected T2 months % titre 104 107 106 expected T3months % titre 108 102 expected

This formulation is chemically stable over 3 months for the 3temperature conditions.

Formulation 3 (Lipoid S75-3+Natrosol):

T0 mg/g 10.29 % titre 96 expected 4° C. T. ambient 40° C. T1 month %titre ND 103 103 expected T2 months % titre 105 100 101 expected T3months % titre 98 107 81 expected

This formulation is chemically stable over 3 months for the 3temperature conditions.

Formulation 2 (Phospholipon 90H):

T0 mg/g 10.93 % titre 102 expected 4° C. T. ambient 40° C. T1 month %titre 99 101 99 expected T2 months % titre 99 99 107 expected T3 months% titre 102 101 104 expected

Formulation 4 (Phospholipon 90H+Natrosol):

T0 mg/g 10.59 % titre 96 expected 4° C. Tambient 40° C. T5 months %titre 101 96 78 expected T9 months % titre 100 96 61 expected

Conclusion

Ivermectin is chemically stable over 3 months under the 3 temperatureconditions: 4° C., room temperature (Tambient) and 40° C., in thenanoemulsions according to the invention.

What is claimed is:
 1. A composition comprising lipid nanocapsules, saidlipid nanocapsules comprising: (a) an oily inner phase consisting ofdiisopropyl adipate and at least one physically and chemically stableavermectin compound solubilized in said diisopropyl adipate; and (b) asurfactant comprising soybean and/or egg lecithin(s) having ahydrogenated phosphatidylcholine content of greater than 70% by weight,said surfactant being lipophilic, solid at room temperature and coatingsaid oily inner phase; said lipid nanocapsules being dispersed in acontinuous hydrophilic phase; said composition being devoid of anysurfactant(s) other than said lecithin(s); said composition being devoidof any organic solvent(s) other than said diisopropyl adipate; saidcomposition being devoid of propenetrating agents; said compositionbeing physically stable at 4° C., ambient temperature and 40° C., for aperiod of two months; said avermectin compound being chemically stablein said composition at 4° C., ambient temperature and 40° C., for aperiod of three months.
 2. The composition as defined by claim 1, saidat least one avermectin compound being selected from the groupconsisting of ivermectin, invermectin, avermectin, abamectin,doramectin, eprinomectin and selamectin.
 3. The composition as definedby claim 1, said lecithin(s) comprising between 0.1 and 10% by weightrelative to the total weight thereof.
 4. The composition as defined byclaim 1, formulated for topical administration.
 5. The composition asdefined by claim 1, said composition being in the form of ananoemulsion.
 6. The composition as defined by claim 1, formulated fororal administration.
 7. The composition as defined by claim 4,formulated as a cream, milk, ointment, impregnated pad, syndet, wipe,gel, spray, foam, lotion, stick, shampoo or cleansing base.
 8. Thecomposition as defined by claim 6, formulated as gelatin capsules,sugar-coated tablets or syrups.
 9. A composition comprising lipidnanocapsules, said lipid nanocapsules comprising: (a) an oily innerphase consisting of diisopropyl adipate and at least one physically andchemically stable avermectin compound solubilized in said diisopropyladipate; and (b) a surfactant comprising soybean and/or egg lecithin(s)having a hydrogenated phosphatidylcholine content of greater than 70% byweight, said surfactant being lipophilic, solid at room temperature andcoating said oily inner phase; said lipid nanocapsules being dispersedin a continuous hydrophilic phase; and said composition furthercomprising a gelling agent which is a cellulose derivative selected fromthe group consisting of methylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,carboxymethylcellulose, hydroxymethylcellulose andhydroxypropylcellulose, and mixtures thereof; said composition beingdevoid of any surfactant(s) other than said lecithin(s); saidcomposition being devoid of any organic solvent(s) other than saiddiisopropyl adipate; said composition being devoid of propenetratingagents; said composition being physically stable at 4° C., ambienttemperature and 40° C., for a period of nine months; said avermectincompound being chemically stable in said composition at 4° C., ambienttemperature and 40° C., for a period of three months.
 10. Thecomposition as defined by claim 9, said lecithin(s) comprising from 0.1to 10% by weight relative to the total weight thereof.
 11. Thecomposition as defined by claim 9, comprising by weight relative to thetotal weight thereof: (a) 0.1 to 5% of lecithin(s); (b) 1 to 20% ofdiisopropyl adipate; (c) 0.1 to 5% of avermectin compound; and (d) up to2% of cellulose derivative.
 12. The composition as defined by claim 9,formulated for topical administration.
 13. The composition as defined byclaim 9, formulated for oral administration.
 14. The composition asdefined by claim 12, formulated as a cream, milk, ointment, impregnatedpad, syndet, wipe, gel, spray, foam, lotion, stick, shampoo or cleansingbase.
 15. The composition as defined by claim 13, formulated as gelatincapsules, sugar-coated tablets or syrups.
 16. A composition comprisinglipid nanocapsules, said lipid nanocapsules comprising: (a) an oilyinner phase consisting of diisopropyl adipate and an avermectin compoundsolubilized in said diisopropyl adipate; and (b) a surfactant comprisingsoybean and/or egg lecithin(s) having a hydrogenated phosphatidylcholinecontent of greater than 70% by weight, said surfactant being lipophilic,solid at room temperature and coating said oily inner phase; said lipidnanocapsules being dispersed in a continuous hydrophilic phase; saidcomposition being devoid of any surfactant(s) other than saidlecithin(s); said composition being devoid of any organic solvent(s)other than said diisopropyl adipate; said composition being devoid ofpropenetrating agents; said composition being physically and chemicallystable at 4° C., ambient temperature and 40° C., for a period of atleast two months.
 17. A composition comprising lipid nanocapsules, saidlipid nanocapsules comprising: (a) an oily inner phase consisting ofdiisopropyl adipate and an avermectin compound solubilized in saiddiisopropyl adipate; and (b) a surfactant comprising soybean and/or egglecithin(s) having a hydrogenated phosphatidylcholine content of greaterthan 70% by weight, said surfactant being lipophilic, solid at roomtemperature and coating said oily inner phase; said lipid nanocapsulesbeing dispersed in a continuous hydrophilic phase; and said compositionfurther comprising a gelling agent which is a cellulose derivativeselected from the group consisting of methylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,carboxymethylcellulose, hydroxymethylcellulose andhydroxypropylcellulose, and mixtures thereof; said composition beingdevoid of any surfactant(s) other than said lecithin(s); saidcomposition being devoid of any organic solvent(s) other than saiddiisopropyl adipate; said composition being devoid of propenetratingagents; said composition being physically and chemically stable at 4°C., ambient temperature and 40° C., for a period of at least threemonths.
 18. A method for the treatment of rosacea, comprisingadministering to an individual in need of such treatment an effectiveamount of the composition as defined by claim
 1. 19. A method forpreparing the composition as defined by claim 1, comprising thefollowing steps: (i) solubilizing at least one avermectin compound indiisopropyl adipate to obtain the oily phase; (ii) mixing hydrophiliccompounds to obtain the hydrophilic phase; (iii) dispersing thelecithin(s) in the oily phase obtained in (i) or in the hydrophilicphase obtained in (ii); (iv) mixing the oily phase with the hydrophilicphase; (v) introducing the mixture obtained in (iv) into a High-PressureHomogenizer, to obtain a nanoemulsion.
 20. A method as defined by claim19, comprising a step (vi) of adding a gelling agent to the nanoemulsionobtained in (v).